It is proposed to study in depth the biochemical basis for the development of liver cancer induced by chemical carcinogens. In particular, we propose to study the role of repair in vivo of the carcinogen damaged DNA and its replication in the development of preneoplastic and neoplastic lesions in the liver induced by N-methyl N-nitroso urea (MNU). The experimental design will aim at (1) inducing the damage on DNA by MNU, (2) stimulating the replication of damaged DNA before repair by partial hepatectomy, and (3) allowing growth of the resulting initiated cells under conditions of a 'selection pressure' conducive only to the growth of the altered cell. Such growth in turn leads to cancer. To achieve these sequential events, a dose of MNU which is non-necrogenic and non-carcinogenic to liver will be administered first to induce DNA damage. Partial hepatectomy will be done to stimulate cell proliferation so that the damaged DNA can replicate. These cells, hopefully replicated with damaged DNA, will be allowed to grow in vivo into preneoplastic and neoplastic lesions by a slight modification of selection procedure developed by Solt and Farber (1). In addition to determining the role of replication of carcinogen-damaged DNA in the induction of preneoplastic and neoplastic lesions, these studies will also aim at correlating the chemical nature of the lesion with the appearance of the preneoplastic and neoplastic cells.